DESCRIPTION (Taken from the application): Total joint replacement implant survival is limited by aseptic loosening of the prosthesis. Implant loosening results from periprosthetic bone resorption which is mediated by a chronic inflammatory response to implant-derived particulate debris. Understanding the basic cellular and molecular events involved in this osteolytic process will introduce potential molecular targets for therapeutic intervention. Previous experiments with genetic blockade of the TNF signaling pathway, prevents experimental, particle-induced osteolysis. Thus, we focus on the nuclear transcription factor kappa B (NF-kB) which is essential for osteoclast formation and is a known mediator of TNF-induced gene transcription. We show in osteoclast precursor cells, that implant particles induce TNF expression and are potent activators of NF-kB. TNF activates NF-kB in these cells via a novel, cell-specific mechanism involving the tyrosine kinase c-src and the NF-kB inhibitory protein (IkB). This suggests that particles may exert their effect via a similar signaling pathway. We hypothesize that in osteoclast precursor cells polymethylmethacrylate (PMMA) particles activate NF-kB via a TNF signaling pathway involving c-src phosphorylation of IkB and that blocking particle-induced NF-kB activation will inhibit osteoclastogenesis in vitro. Our aims are: 1) to determine the mechanism(s) by which PMMA particles induce NF-kB activation in osteoclast precursor cells and 2) to determine the effect of blocking NF-kB activation on PMMA-induced osteoclastogenesis in vitro.